Inhibition of neuronal Ca 2+ influx by gabapentin and pregabalin in the human neocortex

Abstract

Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K +-induced [Ca 2+] i increase in fura-2-loaded human neocortical synaptosomes (IC 50=17 μM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(−)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [ 3H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K +-induced [Ca 2+] i increase was prevented by the P/Q-type voltage-gated Ca 2+ channel blocker ω-agatoxin IVA. The α2 δ-1, α2 δ-2, and α2 δ-3 subunits of voltage-gated Ca 2+ channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K +-evoked release of [ 3H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca 2+ channel α2 δ subunit to selectively attenuate depolarization-induced Ca 2+ influx of presynaptic P/Q-type Ca 2+ channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.